The invention relates to new derivatives of hydantoins, thiohydantoins, pyrimidinediones and thioxopyrimidinones of general formula (I) represented below, their preparation processes and their use as medicaments. These compounds have a good affinity with certain sub-types of somatostatin receptors and therefore have useful pharmacological properties. The invention also relates to the pharmaceutical compositions containing said compounds and their use for the preparation of a medicament intended to treat pathological states or diseases in which one (or more) somatostatin receptors are involved.
Somatostatin (SST) is a cyclic tetradecapeptide which was isolated for the first time from the hypothalamus as a substance which inhibits the growth hormone (Brazeau P. et al., Science 1973, 179, 77-79). It also operates as a neurotransmitter in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995, 16, 427-442). Molecular cloning has allowed it to be shown that the bioactivity of somatostatin depends directly on a family of five receptors linked to the membrane.
The heterogeneity of the biological functions of somatostatin has led to studies which try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which has led to the discovery of 5 sub-types of receptors (Yamada et al., Proc. Natl. Acad. Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are currently being actively studied. The affinities with different sub-types of somatostatin receptors have been associated with the treatment of the following disorders/diseases. Activation of sub-types 2 and 5 has been associated with suppression of the growth hormone (GH) and more particularly with that of adenomas secreting GH (acromegalia) and those secreting hormone TSH. Activation of sub-type 2 but not sub-type 5 has been associated with the treatment of adenomas secreting prolactin. Other indications associated with the activation of sub-types of somatostatin receptors are the recurrence of stenosis, inhibition of the secretion of insulin and/or of glucagon and in particular diabetes mellitus, hyperlipidemia, insensiblity to insulin, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy; inhibition of the secretion of gastric acid and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulae, irritable colon syndrome, dumping syndrome, aqueous diarrhoea syndrome, diarrhoea associated with AIDS, diarrhoea induced by chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumours; the treatment of cancer such as hepatomas; the inhibition of angiogenesis, the treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; angioplasty; the prevention of bleeding of grafted vessels and gastrointestinal bleeding. The agonists of somatostatin can also be used to reduce the weight of a patient.
Among the pathological disorders associated with somatostatin (Moreau J. P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., The European Journal of Medicine, 1993, 2, 97-105), there can be mentioned for example: acromegalia, hypophyseal adenomas, Cushing""s disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison""s syndrome, GRFoma as well as acute bleeding of the esophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage of the gastroduodenal ulcer, Crohn""s disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic fields such as, for example, cephaleas including cephalea associated with hypophyseal tumours, pain, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan""s syndrome, sleep apnea syndrome, Graves"" disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukaemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, as well as Alzheimer""s disease. Osteoporosis can also be mentioned.
The Applicant found that the compounds of general formula (I) described hereafter have an affinity and a selectivity for the somatostatin receptors. As somatostatin and its peptide analogues often have a poor bioavailability by oral route and a low selectivity (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110), said compounds, non-peptide agonists or antagonists of somatostatin, can be advantageously used to treat pathological states or illnesses as presented above and in which one (or more) somatostatin receptors are involved. Preferably, said compounds can be used for the treatment of acromegalia, hypophyseal adenomas or endocrine gastroenteropancreatic tumours including carcinoid syndrome.
The compounds of the present invention correspond to general formula (I) 
in racemic, enantiomeric form or all combinations of these forms, in which:
R1 represents a (C1-C12)alkyl, (C0-C6)alkyl-C(O)xe2x80x94Oxe2x80x94Z1, (C0-C6)alkyl-C(O)xe2x80x94NHxe2x80x94(CH2)pxe2x80x94Z2 or aryl radical optionally substituted,
Z1 represents H, a (C1-C6)alkyl, xe2x80x94(CH2)p-aryl radical;
Z2 represents an amino, (C1-C12)alkylamino, (C3-C8)cycloalkylamino, N,N-di-(C1-C12)alkylamino, NHxe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)p-phenyl, NHxe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)pxe2x80x94(C1-C6)alkyl radical, an optionally substituted carbocyclic or heterocyclic aryl radical or an optionally substituted heterocyclic non aromatic radical;
R2 represents H, (C1-C12)alkyl or aryl optionally substituted;
R3 represents H or (CH2)pxe2x80x94Z3;
Z3 represents (C1-C12)alkyl, (C1-C12)alkenyl, (C3-C8)cycloalkyl, xe2x80x94Y1xe2x80x94(CH2)p-phenyl-(X1)n, xe2x80x94Sxe2x80x94(C1-C12)alkyl, Sxe2x80x94(C1-C12)alkyl-Sxe2x80x94Sxe2x80x94(C1-C12)alkyl, an optionally substituted carbocyclic or heterocyclic aryl radical, and in particular one of the radicals represented below 
xe2x80x83an optionally substituted heterocyclic non aromatic radical, a bis-arylalkyl or di-arylalkyl radical or also the radical 
Y1 represents O, S, NH or is absent;
R4 represents (CH2)pxe2x80x94Z4;
Z4 represents amino, (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, amino(C3-C6)cycloalkyl, amino(C1-C6)alkyl(C3-C6)cycloalkyl(C1-C6)alkyl, carboxylic or heterocyclic aminoaryl, (C1-C12)alkoxy, (C1-C12)alkenyl, Nxe2x80x94C(O)O(C1-C6)alkyl, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below 
xe2x80x83or also Z4 represents an N(R6)(R7) radical in which R6 and R7 taken together with the nitrogen atom which they carry form together a heterocycle with 5 to 7 members;
R5 represents H, xe2x80x94(CH2)pxe2x80x94C(O)xe2x80x94(CH2)pxe2x80x94Z5, xe2x80x94(CH2)pxe2x80x94Z5, xe2x80x94(CH2)pxe2x80x94OZ5 or xe2x80x94(C0-C6)alkyl-C(O)xe2x80x94NHxe2x80x94(CH2)pxe2x80x94Z5,
Z5 representing an optionally substituted radical chosen from the group constituted by the xe2x80x94(C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furannyl, thiophene, isoxazolyl, indolyl radicals, and 
xe2x80x83it being understood that an optionally substituted radical or an optionally substituted phenyl is optionally substituted by one or more substituent, each preferably chosen independently from the group constituted by the Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, xe2x80x94OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, xe2x80x94(CH2)p-phenyl-(X1)q, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6)alkyl, xe2x80x94NHxe2x80x94C(O)Oxe2x80x94(C1-C6)alkyl, xe2x80x94Sxe2x80x94(C1-C6)alkyl, xe2x80x94S-phenyl-(X1)q, xe2x80x94Oxe2x80x94(CH2)p-phenyl-(X1)q, xe2x80x94(CH2)pxe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)pxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94NH2, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94NHxe2x80x94(C1-C6)alkyl, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94N-di-((C1-C6)alkyl) and xe2x80x94((C0-C12))alkyl-(X1)q radicals;
X1, each time that it occurs, is independently chosen from the group constituted by the H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, xe2x80x94OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, xe2x80x94Sxe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)p-amino, xe2x80x94(CH2)pxe2x80x94NHxe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)pxe2x80x94N-di-((C1-C6)alkyl), xe2x80x94(CH2)pxe2x80x94phenyl and xe2x80x94(CH2)pxe2x80x94NHxe2x80x94(C3-C6)cycloalkyl radicals;
p each time that it occurs is independently 0 or an integer from 1 to 6;
q each time that it occurs is independently an integer from 1 to 5.
X represents O or S;
n represents 0 or 1; and finally
when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.
According to a preferred variant of the invention, the compounds of general formula (I) are such that R5 represents H.
The compounds of general formula (I) can, if appropriate, contain more than one asymmetrical centre. If this happens, the diastereomers or any mixture of diastereomers are also included in the invention. For example, when the compound of general formula (I) has two asymmetrical centres, the invention will include the compounds of general formula (I) of xe2x80x9cR,Sxe2x80x9d, xe2x80x9cS,Rxe2x80x9d, xe2x80x9cR,Rxe2x80x9d and xe2x80x9cS,Sxe2x80x9d configurations, as well as a mixture in whatever proportions of the latter.
In the present invention, the alkyl radicals can be linear or branched. By alkyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, unless specified otherwise, is meant a monocyclic carbon system containing 3 to 7 carbon atoms. By alkenyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one unsaturation (double bond). By alkynyl, unless specified otherwise, is meant a linear or branched alkyl radical containing 1 to 6 carbon atoms and having at least one double unsaturation (triple bond). By carbocyclic or heterocyclic aryl, is meant a carbocyclic or heterocyclic system containing at least one aromatic ring, a system being called heterocyclic when at least one of the rings which comprise it contains a heteroatom (O, N or S). By aryl, unless specified otherwise, is meant a carbocyclic system comprising at least one aromatic ring. By haloalkyl, is meant an alkyl radical of which at least one of the hydrogen atoms (and optionally all) is replaced by a halogen atom. By heterocyclic non aromatic radical, is meant a heterocyclic system containing no aromatic ring, at least one of the rings comprising said system containing at least one heteroatom (O, N or S).
By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylamino, alkenyl, alkynyl and aralkyl radicals, is meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkylmino, alkenyl, alkynyl and aralkyl radicals the alkyl radical of which has the meaning indicated previously.
By N,N-di-(C1-C12)alkylamino radical, is meant a dialkylamino radical of which the two alkyl radicals substituting the nitrogen atom can have independently 1 to 12 carbon atoms.
By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By cycloalkyl, is meant in particular the cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexyl and cycloheptanyl radicals. By carbocyclic or heterocyclic aryl, is meant in particular the phenyl, naphthyl, pyridinyl, furannyl, pyrrolyl, thiophenyl, thiazolyl, indanyl, indolyl, imidazolyl, benzofurannyl, benzothiophenyl, phthalimidyl radicals. By carbocyclic or heterocyclic aralkyl, is meant in particular the benzyl, phenylethyl, phenylpropyl, phenylbutyl, indolylalkyl, phthalimidoalkyl radicals.
When an arrow emanates from a chemical structure, said arrow indicates the attachment point. For example: 
represents the aminoethyl radical.
When an arrow is drawn through a bi- or tricyclic group, said arrow indicates that said bi- or tricyclic group can be attached by any of the available attachment points on any aromatic ring of said group. For example: 
represents a radical which is attached at any position on the benzene ring.
In particular, the compounds of general formula (I) according to the invention can be chosen such that:
R1 represents an optionally substituted aryl radical;
R2 represents H or an alkyl radical;
R3 represents one of the following radicals: 
R1 represents one of the following radicals: 
R5 represents H or an alkyl radical.
Preferably, the compounds of general formula (I) are such that:
R1 represents the phenyl radical optionally substituted by a halogen atom or a (C1-C12)alkyl, (C1-C12)alkoxy or nitro radical;
R2 and R5 represent H or alkyl;
R3 represents H or (CH2)pxe2x80x94Z3;
Z3 represents (C1-C12)alkyl, (C3-C8)cycloalkyl, Y1xe2x80x94(CH2)p-phenyl-(X1)n, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below 
Y1 represents O, S, NH or is absent;
R4 represents (CH2)pxe2x80x94Z4;
Z4 represents amino, (C3-C8)cycloalkyl, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, amino(C3-C6)cycloalkyl, amino(C1-C6)alkyl(C3-C6)cycloalkyl(C1-C6)alkyl, carbocyclic or heterocyclic aminoaryl, an optionally substituted carbocyclic or heterocyclic aryl radical, an optionally substituted heterocyclic non aromatic radical, bis-arylalkyl, di-arylalkyl or one of the radicals represented below 
xe2x80x83it being understood that an optionally substituted radical or an optionally substituted phenyl is optionally substituted by one or more substituent, each preferably chosen independently from the group constituted by the Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, xe2x80x94OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, xe2x80x94(CH2)p-phenyl-(X1)q, xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6)alkyl, xe2x80x94NHxe2x80x94C(O)Oxe2x80x94(C1-C6)alkyl, xe2x80x94Sxe2x80x94(C1-C6)alkyl, xe2x80x94S-phenyl-(X1)q, xe2x80x94Oxe2x80x94(CH2)p-phenyl-(X1)q, xe2x80x94(CH2)pxe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)pxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94NH2, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94NHxe2x80x94(C1-C6)alkyl, xe2x80x94Oxe2x80x94(CH2)pxe2x80x94N-di-((C1-C6)alkyl) and xe2x80x94((C0-C12))alkyl-(X1)q radicals;
X1, each time that it occurs, is independently chosen from the group constituted by the H, Cl, F, Br, I, CF3, NO2, OH, NH2, CN, N3, xe2x80x94OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, xe2x80x94Sxe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)p-amino, xe2x80x94(CH2)pxe2x80x94NHxe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)pxe2x80x94N-di-((C1-C6)alkyl), xe2x80x94(CH2)p-phenyl and xe2x80x94(CH2)pxe2x80x94NHxe2x80x94(C3-C6)cycloalkyl radicals;
p each time that it occurs is independently 0 or an integer from 1 to 6;
q each time that it occurs is independently an integer from 1 to 5.
X represents O or S;
n represents 0 or 1; and finally
when n represents 0, m represents 1, 2 or 3, and when n represents 1, m represents 0 or 1.
More preferentially, the compounds of general formula (I) are such that:
R1 represents the phenyl radical optionally substituted by a halogen atom or a (C1-C12)alkyl, (C1-C12)alkoxy or nitro radical;
R2 and R5 represent H or alkyl;
R3 represents (CH2)pxe2x80x94Z3,
Z3 representing a (C3-C8)cycloalkyl radical or an optionally substituted radical chosen from the phenyl, naphthyl, furannyl, thiophene, indolyl, pyrrolyl and benzothiophene radicals;
R4 represents (CH2)pxe2x80x94Z4;
Z4 representing amino, (C1-C2)alkylamino, N,N-di-(C1-C12)alkylamino or amino(C1-C6)alkyl(C3-C6)cycloalkyl-(C1-C6)alkyl;
X represents S;
p each time that it occurs is independently 0 or an integer from 1 to 6;
m represents 0, 1 or 2; and finally
n represents 0 or 1.
Yet more preferentially, the compounds of the present invention are of the compounds:
of general sub-formula (I)a represented below: 
in which:
Rxe2x80x23 represents one of the radicals represented below: 
and Rxe2x80x24 represents one of the radicals represented below: 
of general sub-formula (I)b represented below: 
in which:
Rxe2x80x23 represents one of the radicals represented below: 
and Rxe2x80x24 represents one of the radicals represented below: 
of general sub-formula (I)c represented below: 
in which:
Rxe2x80x23 represents one of the radicals represented below: 
and Rxe2x80x24 represents one of the radicals represented below: 
The invention relates moreover to the preparation processes for the compounds of general formula (I) described previously (also applicable to the corresponding compounds of general sub-formulae (I)a, (I)b and (I)c).
The compounds of general formula (I) described previously for which n represents 0 and X represents O or S can be prepared by the reaction in an aprotic solvent of the compound of general formula (II) represented below 
in which m, R1, R2, R3 and R5 have the same meaning as in general formula (I), and the Oxe2x80x94GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy,
with an isocyanate or isothiocyanate of general formula (III)
xe2x80x83R4xe2x80x94Nxe2x95x90Cxe2x95x90X,xe2x80x83xe2x80x83(III)
xe2x80x83in which R4 and X have the same meaning as in general formula (I),
preferably in the presence of a tertiary base for a duration of approximately 1 to 24 hours and at a temperature preferably comprised between 20 and 60xc2x0 C.
The compounds of general formula (I) described previously for which n represents 1 and X represents O or S can be prepared by the reaction in an aprotic solvent of the compound of general formula (IV) represented below 
in which m, R1, R2, R3 and R5 have the same meaning as in general formula (I), and the Oxe2x80x94GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy,
with an isocyanate or isothiocyanate of general formula (III)
R4xe2x80x94Nxe2x95x90Cxe2x95x90Xxe2x80x83xe2x80x83(III)
xe2x80x83in which R4 and X have the same meaning as in general formula (I),
preferably in the presence of a tertiary base for a duration of approximately 1 to 48 hours and at a temperature preferably comprised between 20 and 70xc2x0 C.
For the above processes, the aprotic solvent is preferably polar and can in particular be THF or dichloromethane. The tertiary base will be for example triethylamine or N,N-diisopropylethylamine.
Moreover the invention offers new synthesis intermediates which are useful for the preparation of the compounds of general formula (I). These compounds, precursors of the compounds of general formula (II) and (IV), correspond to general formula (V): 
in which
R1, R2, R5, m and n have the same meaning as in general formula (I);
and the Oxe2x80x94GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy.
The following compounds corresponding to general formula (V) are the preferred intermediates:
benzyl (2S)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoate;
benzyl (2R)-2-amino-3-[(4-phenyl)-1H-imidazol-2-yl]propanoate;
benzyl (2S)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate;
benzyl (2R)-2-amino-4-[(4-phenyl)-1H-imidazol-2-yl]butanoate;
benzyl (3R)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoate;
benzyl (3S)-3-amino-4-[(4-phenyl)-1H-imidazol-2-yl]propanoate.
A subject of the invention is also, as medicaments, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts. It also relates to the pharmaceutical compositions containing said compounds or their pharmaceutically acceptable salts, and their use for the preparation of a medicament intended to treat the pathological states or diseases in which one (or more) of the somatostatin receptors are involved.
In particular, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas, Cushing""s disease, gonadotrophinomas and prolactinomas, catabolic side-effects of glucocorticoids, insulin dependent diabetes, diabetic retinopathy, diabetic nephropathy, syndrome X, dawn phenomena, angiopathy, angioplasty, hyperthyroidism, gigantism, endocrinic gastroenteropancreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison""s syndrome, GRFoma as well as acute bleeding of the esophageal varices, ulcers, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulae but also diarrhoeas, refractory diarrhoeas of acquired immunodeficiency syndrome, chronic secretary diarrhoea, diarrhoea associated with irritable bowel syndrome, diarrhoeas induced by chemotherapy, disorders linked with gastrin releasing peptide, secondary pathologies with intestinal grafts, portal hypertension as well as haemorrhages of the varices in patients with cirrhosis, gastro-intestinal haemorrhage, haemorrhage of the gastroduodenal ulcer, bleeding of grafted vessels, Crohn""s disease, systemic scleroses, dumping syndrome, small intestine syndrome, hypotension, scleroderma and medullar thyroid carcinoma, illnesses linked with cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as pancreatic cancer and colorectal cancer, fibroses and more particularly fibrosis of the kidney, fibrosis of the liver, fibrosis of the lung, fibrosis of the skin, also fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and in other therapeutic fields, cephaleas including cephalea associated with hypophyseal tumours, pain, inflammatory disorders such as arthritis, panic attacks, chemotherapy, cicatrization of wounds, renal insufficiency resulting from delayed development, hyperlipidemia, obesity and delayed development linked with obesity, delayed uterine development, dysplasia of the skeleton, Noonan""s syndrome, sleep apnea syndrome, Graves"" disease, polycystic disease of the ovaries, pancreatic pseudocysts and ascites, leukaemia, meningioma, cancerous cachexia, inhibition of H pylori, psoriasis, chronic rejection of allografts as well as Alzheimer""s disease and finally osteoporosis.
Preferably, the compounds of general formulae (I), (I)a, (I)b and (I)c described previously or their pharmaceutically acceptable salts can be used for the preparation of a medicament intended to treat the pathological states or diseases chosen from the group comprising the following pathological states or diseases: acromegalia, hypophyseal adenomas or endocrinic gastroenteropancreatic tumours including carcinoid syndrome, and gastrointestinal bleeding.
By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartarate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate, oxalate and stearate.
The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cPharmaceutical saltsxe2x80x9d, J. Pharm. Sci. 66:1 (1977).
The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water. The suspensions contain in particular suspensions of sustained release microparticles loaded with active ingredient (in particular microparticles of polylactide-co-glycolide or PLGAxe2x80x94cf. for example the Patents U.S. Pat. No. 3,773,919, EP 52 510 or EP 58 481 or the Patent Application PCT WO 98/47489), which allow the administration of a determined daily dose over a period of several days to several weeks.
The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg to 10 g according to the type of active compound used.
These compounds are prepared according to the following procedures.
General Procedure:
i) Cyclization in Order to Obtain the Imidazole Group:
An amino acid is converted to its cesium salt using cesium carbonate in a polar solvent such as a DMF/H2O (1:1) or EtOH/H2O (1:1) mixture. An ester is then obtained using an appropriate bromoketone in an aprotic polar solvent such as anhydrous DMF. The cesium bromide formed is eliminated by filtration and ammonium acetate is added in an aprotic solvent having a high boiling temperature such as xylene or toluene or in an acidic aprotic solvent such as acetic acid. The mixture is maintained under reflux using a Dean-Stark trap for 30 minutes to one hour. In the diagram directly below, PG1 is a protective group, preferably a carbamate, such as t-Boc or benzylcarbamate, and PG2 is also a protective group, preferably a benzyl group. 
ii) N-Substitution on the Imidazole Group:
If appropriate, the N-substitution on the imidazole group is carried out by the reaction described hereafter for the compounds of general formula (I) for which R5 does not represent H.
A solution of the intermediate obtained in the preceding stage, an alkylating agent such as an -bromoketone, an -bromoester, an alkyl or aryl bromide, is heated to a temperature of 20 to 80xc2x0 C. for a duration of 2 to 48 hours in the presence of an organic or inorganic base (optionally supported on a resin such as polystyrene resin), in an aprotic solvent such as THF, acetonitrile or DMF.
Preparation of Benzyl (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate 
A solution of Boc-L-Asp-OBn (12 g; 37.1 mmol) and cesium carbonate (6.05 g; 0.5 eq.) is stirred for approximately 30 minutes at approximately 20xc2x0 C. in EtOH/H2O (1:1, 7 ml), then concentrated under reduced pressure at approximately 40xc2x0 C.
25 ml of a solution of 2-bromoacetophenone (7.38 g; 1 eq.) in dry DMF is added to the resulting salt dissolved in 130 ml of dry DMF. The mixture is stirred for approximately 1 hour at approximately 20xc2x0 C. under an argon atmosphere then concentrated under reduced pressure. Ethyl acetate is added (100 ml) and the mixture filtered, CsBr being washed with ethyl acetate. The filtrate is then concentrated under reduced pressure.
A solution of the residue obtained and ammonium acetate (58 g; 20 eq.) in xylene (280 ml) is maintained under reflux for approximately 30 minutes at approximately 140xc2x0 C. The excess NH4OAc and water are eliminated using a Dean-Stark trap. The progress of the reaction is monitored by thin layer chromatography (TLC; eluent:ethyl acetate/heptane 1:1). The mixture is then taken to approximately 20xc2x0 C. then washed successively with water, a saturated solution of NAHCO3 solution until a basic pH is obtained then with salt water until a neutral pH is obtained. The organic phase is then dried over Na2SO4 and concentrated under reduced pressure.
Purification of the resulting residue by flash chromatography on silica gel (eluent:ethyl acetate/heptane 1:1) yields the expected compound (8.2 g; 52%).
NMR (1H, 400 MHz, CDCl3): 7.64-7.14 (m, 11H, arom H); 5.95 (d, 1H, NHBoc); 5.21-5.13 (AB, 2H, OCH2Ph, JAB=12Hz); 4.73 (m, 1H, CH); 3.30 (m, 2H, CH2); 1.42 (s, 9H, (CH3)3C). MS/LC: calculated MM=421.2; m/z=422.2 (M+H).
The following compounds are prepared in an analogous fashion to the procedure described for benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate: 

General procedure: the imidazolyl derivatives protected by N-Boc are treated with a organic or inorganic acid such as trifluoroacetic acid or hydrogen chloride (aqueous or in gaseous form) in an aprotic solvent such as dichloromethane or ethyl acetate at a temperature comprised between 0xc2x0 C. and 25xc2x0 C. for 0.5 to 5 hours.
Preparation of the Dihydrochloride of Benzyl (3S)-3-(4-Phenyl-1H-imidazol-2-yl)-3-amino-propanoate 
A flow of dry HCl is passed through a solution of benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-[(tert-butoxycarbonyl)amino propanoate (5 g) in ethyl acetate (120 ml) at 0xc2x0 C. until the TLC (eluent: 100% ethyl acetate) shows that the starting compound has completely disappeared. The resulting mixture is then evaporated under reduced pressure. Diethylether is added to the solid obtained and the mixture is filtered. The hydrochloride is washed several times with dichloromethane then diethylether and dried under reduced pressure to produce 4.6 g of expected compound (98% yield).
NMR (1H, 400 MHz, DMSOd6): 9.21 (broad s, 2H, NH); 8.03-7.28 (m, arom. H, 11H); 5.10 (s, 1H, OCH2Ph); 5.04 (m, 1H, CH); 3.61 (dd, 1H, CH2, 3J=9 Hz, 2J=17.0 Hz); 3.39 (dd, 1H, CH2xe2x80x2, 3J=5.5 Hz, 2J=17.0 Hz). MS/LC: Calculated MM=321.2; m/z=322.1 (M+H).
The following compounds are prepared in an analogous fashion to the procedure described for the dihydrochloride of benzyl (3S)-3-(4-phenyl-1H-imidazol-2-yl)-3-amino-propanoate. 

General procedure: A free amine of formula (a) or (b) is treated with an aldehyde in a protic or aprotic solvent, preferably dichloromethane or tetrahydrofuran, for a duration of 1 to 15 hours at 20-50xc2x0 C. The resulting imine is then reduced using a reducing agent, preferably sodium triacetoxyborohydride or sodium cyanoborohydride with or without the presence of an acid such as acetic acid, at a temperature comprised between 20 and 50xc2x0 C. for a duration of 0.2 to 5 hours. The N-alkylated compound is isolated by adding water and extraction followed by flash chromatography on silica gel or by crystallization.
Preparation of Benzyl (2S)-4-(4-Phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butanoate 
Thiophene-3-carboxaldehyde (1 ml; 1 eq.) is added to a solution of benzyl (2S)-2-amino-4-(4-phenyl-1H-imidazol-2-yl)butanoate in the form of a free base (3.6 g; 1 eq.) in tetrahydrofuran (hereafter THF, 40 ml). The mixture is stirred for 15 hours at approximately 20xc2x0 C. and diluted by adding 50 ml of tetrahydrofuran. NaBH(OAc)3 (4.73 g; 2 eq.) is then added. After 1 hour of stirring at approximately 20xc2x0 C., the reaction is stopped by adding water (40 ml) and ethyl acetate is then added (100 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40xc2x0 C. Flash chromatography purification on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound in the form of a yellow oil (3.08 g; 66% yield).
NMR (1H, 400 MHz, CDCl3): 7.62-7.04 (m, 15H, arom. H, NH); 5.18 (s, 2H, OCH2); 3.87-3.69 (AB, 2H, CH2NH, 2JAB=13 Hz); 3.38 (dd, 1H, CHNH, 3J=4.5 Hz, 2J=8.5 Hz); 2.98 (m, 1H, CH2CH); 2.88 (m, 1H, CH2CH); 2.17 (m, 1H, CH2); 1.97 (m, 1H, CH2). MS/LC: Calculated MM=431.2; m/z=432.2 (M+H); m/z=430.8 (Mxe2x88x92H).
The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for benzyl (2S)-4-(4-phenyl-1H-imidazol-2-yl)-2-[(3-thienylmethyl)amino]butanoate: 
In the above formulae, R3 represents one of the following radicals: 

General Procedure:
An amine of formula (II), in which m, R1, R2, R3 and R5 have the same meanings as in general formula (I) and the Oxe2x80x94GP radical is a parting protective group derived from an alcohol and in particular benzyloxy, methoxy or tert-butoxy, is treated with an isocyanate or a isothiocyanate of general formula R4xe2x80x94NCX in which R4 has the same meaning as in general formula (I), in the presence or in the absence of a tertiary base such as triethylamine or N,N-diisopropylethylamine, in an aprotic solvent, preferably tetrahydrofuran or dichloromethane, at a temperature comprised between approximately 20 and 60xc2x0 C. and for 1 to 24 hours. The resulting hydantoin or thiohydandoin can be isolated with a yield of 60 to 95%, either by flash chromatography on silica gel or by addition to the reaction mixture of a nucleophilic reagent carried by a polymer such as for example an aminomethylpolystyrene resin (acquired from Novabiochem) followed by filtration and evaporation of the filtrate.
When R4 represents a radical comprising a primary amino termination (for example R4 represents aminoethyl, aminopropyl, etc.), the reagent is not R4xe2x80x94NCX but the corresponding compound the amino group of which is protected by a suitable protective group, for example a tert-butoxycarbonyl group. A subsequent deprotection stage (carried out under standard conditions, namely an acid treatment) must therefore be carried out in order to obtain the compound of general formula (I).
Preparation of Certain Non-commercial Isothiocyanates of General Formula (III): 
These compounds are prepared as follows: a primary amine of general formula R4xe2x80x94NH2 is treated with a mixture of carbon disulphide and N-cyclohexylcarbodiimide N-methyl polystyrene resin, in an aprotic solvent, preferably tetrahydrofuran or dichloromethane, for a duration of 1 hour to 18 hours at 20-50xc2x0 C. The resulting isothiocyanate is isolated after filtration on frit and evaporation of the filtrate.
Preparation of 6-Isothiocyanato-N,N-dimethyl-1-hexanamine 
Carbon disulphide (8.3 mL, 10 eq) and a solution of N,N-dimethyl-1,6-hexanediamine (2g, 1 eq) in THF (10 mL) are added successively dropwise to a suspension of N-cyclohexylcarbodiimide N-methyl polystyrene resin (7.8 g, 1.1 eq; acquired from Novabiochem, load 1.95 mmol/g) in anhydrous THF (120 mL). The suspension is stirred for 2 hours at approximately 20xc2x0 C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40xc2x0 C. in order to produce the expected isothiocyanate derivative (2.6 g, 93% yield).
NMR 1H, 400 MHz, CDCl3,): 3.50 (t, 2H); 2.24 (t, 2H), 2.20 (s, 6H), 1.68 (q, 2H), 1.50-1.31 (m, 6H).
The following compounds are prepared in an analogous fashion to the procedure described for 6-isothiocyanato-N,N-dimethyl-1-hexanamine: 
Preparation of (5S)-1-(1H-Indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-2-thioxo-4-imidazolidinone 
4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20xc2x0 C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 xcexcl). The mixture is stirred for 15 hours at approximately 20xc2x0 C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40xc2x0 C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).
NMR (1H, 400 MHz, CDCl3): 8.24-7.09 (m, 17H, arom H, NH); 5.88, 4.64 (AB, 2H, CH2N, 2JAB=15 Hz); 3.38 (dd, 1H, CH, 3J=3.0 Hz, 2J=8.5 Hz); 2.92 (m, 2H, CH2CH); 2.74 (m, 1H, CH2); 2.24 (m, 1H, CH2). MS/LC: Calculated MM=536.2; m/z=537.1 (M+H).
The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (5S)-1-(1H-indol-3-ylmethyl)-3-(4-nitrophenyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-2-thioxo-4-imidazolidinone (apart from the final purification by flash chromatography on silica gel which is optional): 
In the above formulae, R3 represents one of the following radicals: 
and R4 represents one of the following radicals: 
Preparation of (5S)-1-(1H-Indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione 
3-trifluoromethyl-phenylisocyanate (11 mg, 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (23 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 2 hours at approximately 20xc2x0 C. then diluted with 2 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 xcexcl). The mixture is stirred for 15 hours at approximately 20xc2x0 C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40xc2x0 C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine) in order to produce the expected compound (25 mg, 92% yield).
NMR (1H, 400 MHz, CDCl3): 7.75-6.99 (m, 17H, arom H, NH); 5.25, 4.44 (AB, 2H, CH2N, JAB=15 Hz); 3.77 (m, 1H, CH); 2.92 (m, 1H, CH2CH); 2.88 (m, 1H, CH2CH); 2.72 (m, 1H, CH2); 2.17 (m, 1H, CH2). MS/LC: Calculated MM=543.2; m/z=544.2 (M+H).
The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (5S)-1-(1H-indol-3-ylmethyl)-5-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione: 
In the above formulae, R3 represents one of the following radicals: 
and R4 represents one of the following radicals: 

General Procedure:
An amine of general formula (IV), in which m, R1, R2, R3 and R5 have the same meanings as in general formula (I) and the Oxe2x80x94GP radical is a parting protective group derived from alcohol and in particular benzyloxy, methoxy or tert-butoxy, is treated with an isocyanate or isothiocyanate R4xe2x80x94NCX in the presence of a tertiary base such as triethylamine or N,N-diisopropylethylamine in an aprotic solvent, preferably THF or dichloromethane, at a temperature comprised between 20 and 70xc2x0 C. for 1 to 48 hours. The compound obtained can be isolated with a yield of 40 to 90%, either by flash chromatography on silica gel or by addition to the reaction mixture of a nucleophilic reagent carried by a polymer such as for example an aminomethylpolystyrene resin (acquired from Novabiochem) followed by filtration and evaporation of the filtrate.
When R4 represents a radical comprising a primary amino termination (for example: R4 represents aminoethyl, aminopropyl, etc.), the reagent is not R4xe2x80x94NCX but the corresponding compound the amino group of which is protected by a suitable protective group, for example a tert-butoxycarbonyl group. A subsequent deprotection stage (carried out under standard conditions, namely an acid treatment) must therefore be carried out in order to obtain the compound of general formula (I).
Preparation of (6S)-1-(1H-Indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl)-2-thioxotetrahydro-4(1H)-pyrimidinone 
Propylisothiocyanate (25 xcexcl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (90 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 15 hours at a temperature of approximately 40xc2x0 C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added. The mixture is stirred for 5 hours at a temperature of approximately 20xc2x0 C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40xc2x0 C. 1 ml of THF and 1 ml of triethylamine are added to the residue. The mixture is stirred for 15 hours at a temperature of approximately 40xc2x0 C. then concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) yields the expected compound (72 mg, yield 82%).
NMR (1H, 400 MHz, CDCl3): mixture of 2 atropisomers: 8.69-6.45 (m, 12H, H arom, NH); 6.42, 4.89 (AB, 1H, CH2, JAB=14.5 Hz); 5.78, 5.42 (AB, 1H, CH2, JAB=14.5 Hz); 4.99 (m, 1H, CH); 4.41-4.36 (m, 1H, CH2); 4.20-4.11 (m, 1H, CH2); 3.49, 2.94 (AB, 1H, CH2CO, JAB=16 Hz); 3.28, 2.80 (AB, 1H, CH2CO, JAB=16 Hz); 1.52 (m, 1H, CH2); 1.40 (m, 1H, CH2); 0.76, 0.62 (2m, 3H, CH3). MS/LC: Calculated MM=443.2; m/z=444.2 (M+H).
The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-1-(1H-indol-3-ylmethyl)-3-propyl-6-(4-phenyl-1H-imidazol-2-yl)-2-thioxotetrahydro-4(1H)-pyrimidinone (except for the final purification by flash chromatography on silica gel which is optional): 
In the above formula, R3 represents one of the following radicals: 
and R4 represents one of the following radicals: 
Preparation of (6S)-1-(1H-Indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H-imidazol-2-yl)dihydro-2.4(1H,3H)-pyrimidinedione 
4-methoxyphenylisocyanate (40 xcexcl, 1.2 eq.) is added to a solution of benzyl (3S-3-[(1H-indol-3-ylmethyl)amino]-3-(4-phenyl-1H-imidazol-2-yl)propanoate (100 mg, 1 eq.) in THF (2 ml). The mixture is stirred for 5 hours at a temperature of approximately 20xc2x0 C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 138 mg, 2 eq.) is added. The mixture is stirred for 3 hours at a temperature of approximately 20xc2x0 C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40xc2x0 C. 2 ml of THF and 2 ml of triethylamine are added to the residue. The mixture is taken to reflux for 24 hours then concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2) yields the expected compound (80 mg, yield 74%.
NMR (1H, 400 MHz, CDCl3): mixture of 2 atropisomers: 9.67-8.96 (2s, 1H, NH); 8.49 (s, 1H, NH); 5.15, 4.36 (AB, 1H, CH2, JAB=15 Hz); 5.08, 4.69 (AB, 1H, CH2, JAB=15 Hz); 4.67, 4.57 (2m, 1H, CH); 3.72 (s, 3H, OCH3); 3.29-2.79 (m, 2H, CH2CO). MS/LC: Calculated MM=491.2; m/z=492.3 (M+H).
The following compounds (in their two enantiomer forms) are prepared in an analogous fashion to the procedure described for (6S)-1-(1H-indol-3-ylmethyl)-3-(4-methoxyphenyl)-6-(4-phenyl-1H-imidazol-2-yl)dihydro-2.4(1H,3H)-pyrimidinedione (except for the final purification by flash chromatography on silica gel which is optional): 
In the above formula, R3 represents one of the following radicals: 
and R4 represents one of the following radicals: 